The present invention relates to optically active cephalosporin analogs and, more particularly, it pertains to optically active compounds of cephalosporin analogs represented by the general formula (I) ##STR3## wherein R.sub.1 represents a hydrogen, a lower alkyl group or a lower acyl group, R.sub.2 represents a hydrogen or a protective group of carboxylic acid, Q represents a hydrogen or a halo group selected from bromo, chloro, fluoro and iodo, A.sub.2 represents a hydrogen, a lower alkyl group, a lower alkenyl group, a lower alkinyl group, a cycloalkyl group or an aryl group, those groups being unsubstituted or substituted with suitable substituent(s) which are selected from carboxyl group, cyano group, a halo group, carbamoyl group and a lower alkyloxycarbonyl group, and the hydrogens at the 6- and 7-positions have cis configuration and pharmaceutically acceptable salts thereof.
Heretofore, a carbacephem compound, which is named according to the nomenclature in J. Am. Chem. Soc. 96, 7584 (1974), wherein the sulfur atom of cephalosporin is substituted with a carbon atom and which has a substituted methyl group at the 3-position is described in the above reference and J. Med. Chem. 20, 551 (1977). However, no compound having especially strong antibacterial activity has been reported. In Japanese Published Unexamined Patent Application No. 9296/79 (German Offenlegungsschrift No. 2716707), a carbacephem compound with a 2-aminothiazol-4-yl-2-synmethoxyimino acetamido group but having no substituents at the 4-position is mentioned but neither practical embodiment for preparing the compound nor antibacterial activity thereof is described in the reference.
The present inventors have succeeded in preparing carbacephem compounds having various substituents at the 4-, 5- or 3-position, numbering system of which is as shown in formula (I). The compounds are described in the specifications of Japanese Published Unexamined Patent Application No. 128591/79, G.O. No. 2911786, Japanese Patent Application No. 162008/78 now Japanese Published Unexamined Patent Application No. 87791/80 and U.S. patent application Ser. No. 23,645 filed on Mar. 23, 1979. "G.O." refers to German Offenlegungsschrift hereinafter.
Furthermore, the present inventors have succeeded in preparing novel acylated carbacephems which are new antibiotics having strong antibacterial activities. The compounds are described in the specification of Japanese Published Unexamined Patent Application No. 128591/79, G.O. No. 2911787, U.S. patent application Ser. No. 23,646 and Japanese Patent Application No. 162008/78 now Japanese Published Unexamined Patent Application No. 87791/80.
Among the compounds which are provided by the present inventors and represented by the general formula (II) ##STR4## (wherein X' is an acyl group employed in the chemistry of cephalosporins and penicillins, R'.sub.1 represents a hydrogen atom, a lower alkyl group or a lower acyl group, and R'.sub.2 represents a hydrogen atom or an ester-protecting group conventionally employed in the field of the chemistry of penicillins and cephalosporins, that is, an alkyl group having 1 to 5 carbon atoms such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, etc., a halogenated alkyl group having 1 to 5 carbon atoms such as chloromethyl group, 2,2,2-trichloroethyl group, 2,2,2-trifluoroethyl group, etc., an arylmethyl group having 7 to 20 carbon atoms such as benzyl group, diphenylmethyl group, triphenylmethyl group, etc., an arylmethyl group having 7 to 20 carbon atoms and having methoxy group, nitro group, etc. on the phenyl ring, a substituted silyl group such as trimethylsilyl group or triphenylsilyl group or a group enzymatically or nonenzymatically readily eliminable in vivo, for example, a group represented by the general formula ##STR5## wherein R.sub.4 represents a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, R.sub.3 represents a lower alkyl group having 1 to 6 carbon atoms, a lower alkoxy group having 1 to 6 carbon atoms or phenyl group, etc.), the acyl compound represented by the formula (I') ##STR6## (wherein R.sub.1, R.sub.2 and A.sub.2 have the same meanings as defined above, B represents an unsaturated six membered carbocycle which is selected from cyclohexenyl group, cyclohexadienyl group and phenyl group or a five or six membered heterocycle, A.sub.1 represents substituent(s) which is selected from hydrogen atom, hydroxyl group, a lower alkoxy group having 1 to 4 carbon atoms, a halo group, nitro group, amino group, aminoethyl group, methylsulfonamide group and a lower acyloxy group having 1 to 4 carbon atoms, and n is a number of 0 to 5) which has the carbacephem ring represented by the formula (III) (shown below) are reported to have strong antimicrobial activity against Gram-positive and Gram-negative microorganisms in Japanese Patent Application Nos. 122402/78, 133071/78, 162006/78, published respectively as Japanese Published Unexamined Patent Application Nos. 49375/80, 59185/80, 87789/80 and 87790/80, 162007/78 (German Offenlegungsschrift 2911787), etc. Especially the acyl compounds having the carbacephem ring represented by the general formula (I") ##STR7## wherein A.sub.2 and Q have the same significance as defined above, R".sub.1 represents a hydrogen or a methyl group and OA.sub.2 has syn configuration are reported to have strong antimicrobial activity against Gram-positive and Gram-negative microorganisms in the aforementioned patent applications. Hereinafter, compounds represented by the general formula (I), (II), (III), . . . are identified as Compound [I], Compound [II], Compound [III], . . . , respectively.
Since cephalosporin analogs mentioned above are prepared by totally synthetic methods using optically inactive starting materials are reagents, they are optically inactive unless they have a certain optically active acyl group such as D-phenylglycyl group described in the specification of Japanese Patent Application No. 162006/78, now Japanese Published Unexamined Patent Application No. 87789/80, and U.S. patent application Ser. No. 23,646 (German Offenlegungsschrift No. 2911787).
Accordingly, there is a demaned for optically active analogs and methods for production thereof. To this end, it has now been found that certain optically active cephalosporin compounds can be prepared which have unexpectedly increased biological activity.